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Clinical Roles of Interleukin-6 and STAT3 in Oral Squamous Cell Carcinoma

  • Original Article
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Pathology & Oncology Research

Abstract

The effect inflammation has on cancer prognosis is marked by the presence of cytokines and chemokines. Interleukin-6 (IL-6) is one a multifunctional cytokine that regulates inflammatory responses. We investigated the roles of IL-6 and STAT3 and examined the relationship between IL-6 signaling and clinicopathological factors in patients with oral squamous cell carcinoma (OSCC). We retrospectively examined 116 patients who underwent radical surgery for OSCC. IL-6 and STAT3 expression were detected by immunohistochemistry. IL-6 and STAT3 positivity were detected by IHC, at 78.4 and 80.2 %, respectively. IL-6 expression was significantly associated with pattern of invasion (P = 0.004), vascular invasion (P = 0.003), and pathological nodal status (P = 0.019). Multivariate logistic regression analysis revealed that IL-6 expression was significantly associated with vascular invasion (P = 0.044). Meanwhile, there was no significant association between STAT3 expression and clinicopathological factors and no significant relationship between IL-6 and STAT3 expression. IL-6 expression was significantly associated with 5-year disease-free survival. These results suggest that IL-6 is involved in lymphangiogenesis and recurrence in OSCC.

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References

  1. Fitzmaurice C, Dicker D, Pain A et al (2015) The global burden of cancer 2013. JAMA Oncol 1:505–527

    Article  PubMed  Google Scholar 

  2. Rogers SN, Brown JS, Woolgar JA et al (2009) Survival following primary surgery for oral cancer. Oral Oncol 45:201–211

    Article  PubMed  Google Scholar 

  3. Turcotte S, Rosenberg SA (2011) Immunotherapy for metastatic solid cancers. Adv Surg 45:341–360

    Article  PubMed  PubMed Central  Google Scholar 

  4. Bell RB, Leidner R, Feng Z et al (2015) Developing an immunotherapy strategy for the effective treatment of oral, head and neck squamous cell carcinoma. J Oral Maxillofac Surg 73:S107–S115

    Article  PubMed  Google Scholar 

  5. Chen HH, Chen IH, Liao CT et al (2011) Preoperative circulating C-reactive protein levels predict pathological aggressiveness in oral squamous cell carcinoma: a retrospective clinical study. Clin Otolaryngol 36:147–153

    Article  PubMed  Google Scholar 

  6. Huang SF, Wei FC, Liao CT et al (2012) Risk stratification in oral cavity squamous cell carcinoma by preoperative CRP and SCC antigen levels. Ann Surg Oncol 19:3856–3864

    Article  PubMed  Google Scholar 

  7. Fang HY, Huang XY, Chien HT et al (2013) Refining the role of preoperative C-reactive protein by neutrophil/lymphocyte ratio in oral cavity squamous cell carcinoma. Laryngoscope 123:2690–2699

    Article  CAS  PubMed  Google Scholar 

  8. Culig Z (2013) Interleukin-6 as a therapy target in oral squamous carcinoma. Expert Opin Ther Targets 17:53–59

    Article  CAS  PubMed  Google Scholar 

  9. Jinno T, Kawano S, Maruse Y et al (2015) Increased expression of interleukin-6 predicts poor response to chemoradiotherapy and unfavorable prognosis in oral squamous cell carcinoma. Oncol Rep 33:2161–2168

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Sato J, Ohuchi M, Wada M et al (2015) Differences in sequential posttreatment salivary IL-6 levels between patients with and patients without locoregional recurrences of oral squamous cell carcinoma: part III of a cohort study. Oral Surg Oral Med Oral Pathol Oral Radiol 120:751–760

    Article  PubMed  Google Scholar 

  11. Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420:860–867

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Yu H, Kortylewski M, Pardoll D (2007) Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment. Nat Rev Immunol 7:41–51

    Article  CAS  PubMed  Google Scholar 

  13. Heikkilä K, Ebrahim S, Lawlor DA (2007) A systematic review of the association between circulating concentrations of C reactive protein and cancer. J Epidemiol Community Health 61:824–833

    Article  PubMed  PubMed Central  Google Scholar 

  14. Allin KH, Bojesen SE, Nordestgaard BG (2009) Baseline C-reactive protein is associated with incident cancer and survival in patients with cancer. J Clin Oncol 27:2217–2224

    Article  CAS  PubMed  Google Scholar 

  15. Yu H, Pardoll D, Jove R (2009) STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 9:798–809

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Kruse AL, Luebbers HT, Gratz K et al (2010) C-reactive protein levels: a prognostic marker for patients with head and neck cancer? Head Neck Oncol 2:21

    Article  PubMed  PubMed Central  Google Scholar 

  17. Neurath MF, Finotto S (2011) IL-6 signaling in autoimmunity, chronic inflammation and inflammation-associated cancer. Cytokine Growth Factor Rev 22:83–89

    Article  CAS  PubMed  Google Scholar 

  18. Paramanathan A, Saxena A, Morris DL (2014) A systematic review and meta-analysis on the impact of pre-operative neutrophil lymphocyte ratio on long term outcomes after curative intent resection of solid tumours. Surg Oncol 23:31–39

    Article  PubMed  Google Scholar 

  19. Perisanidis C, Kornek G, Poschl PW et al (2013) High neutrophil-to-lymphocyte ratio is an independent marker of poor disease-specific survival in patients with oral cancer. Med Oncol 30:334

    Article  PubMed  Google Scholar 

  20. de Oliveira MV, Fraga CA, Gomez RS et al (2009) Immunohistochemical expression of interleukin-4, −6, −8, and −12 in inflammatory cells in surrounding invasive front of oral squamous cell carcinoma. Head Neck 31:1439–1446

    Article  PubMed  Google Scholar 

  21. Guo Y, Xu F, Lu T et al (2012) Interleukin-6 signaling pathway in targeted therapy for cancer. Cancer Treat Rev 38:904–910

    Article  CAS  PubMed  Google Scholar 

  22. Tawara K, Oxford JT, Jorcyk CL et al (2011) Clinical significance of interleukin (IL)-6 in cancer metastasis to bone: potential of anti-IL-6 therapies. Cancer Manag Res 3:177–189

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Yoshimura A (2006) Signal transduction of inflammatory cytokines and tumor development. Cancer Sci 97:439–447

    Article  CAS  PubMed  Google Scholar 

  24. Mali SB (2015) Review of STAT3 (signal transducers and activators of transcription) in head and neck cancer. Oral Oncol 51:565–569

    Article  CAS  PubMed  Google Scholar 

  25. Sobin LH, Gospodarowicz MK, Wittekind C (2009) International Union against Cancer (UICC) TNM classification of malignant tumors. 7th ed. Wiley-Blackwell, Oxford

  26. Bryne M, Koppang HS, Lilleng R et al (1992) Malignancy grading of the deep invasive margins of oral squamous cell carcinomas has high prognostic value. J Pathol 166:375–381

    Article  CAS  PubMed  Google Scholar 

  27. Shinriki S, Jono H, Ueda M et al (2011) Interleukin-6 signaling regulates vascular endothelial growth factor-C synthesis and lymphangiogenesis in human oral squamous cell carcinoma. J Pathol 225:142–150

    Article  CAS  PubMed  Google Scholar 

  28. Yadav A, Kumar B, Datta J et al (2011) IL-6 promotes head and neck tumor metastasis by inducing epithelial-mesenchymal transition via the LAK-STAT3-SNAIL signaling pathway. Mol Cancer Res 9:1658–1667

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Otrock ZK, Makarem JA, Shamseddine AI (2007) Vascular endothelial growth factor family of ligants and receptors: review. Blood Cells Mol Dis 38:258–268

    Article  CAS  PubMed  Google Scholar 

  30. Omoto I, Matsumoto M, Okumura H et al (2014) Expression of vascular endothelial growth factor-C and vascular endothelial growth factor receptor-3 in esophageal squamous cell carcinoma. Oncol Lett 7:1027–1032

    PubMed  PubMed Central  Google Scholar 

  31. Arinaga M, Noguchi T, Takeno S et al (2003) Clinical significance of vascular endothelial growth factor C and vascular endothelial growth factor receptor 3 in patients with nonsmall cell lung carcinoma. Cancer 97:457–464

    Article  CAS  PubMed  Google Scholar 

  32. Wakisaka N, Hirota K, Kondo S et al (2012) Induction of lymphangiogenesis through vascular endothelial growth factor-C/vascular endothelial growth factor receptor 3 axis and its correlation with lymph node metastasis in nasopharyngeal carcinoma. Oral Oncol 48:703–708

    Article  CAS  PubMed  Google Scholar 

  33. Duffy SA, Taylor JMG, Terrell JE et al (2008) Interleukin-6 predicts recurrence and survival among head and neck cancer patients. Cancer 113:750–757

    Article  PubMed  Google Scholar 

  34. Jablonska J, Leschner S, Westphal K et al (2010) Neutrophils responsive to endogenous IFN-beta regulate tumor angiogenesis and growth in a mouse tumor model. J Clin Invest 120:1151–1164

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Li MX, Liu XM, Zhang XF et al (2014) Prognostic role of neutrophil-to-lymphocyte ratio in colorectal cancer: a systematic review and meta-analysis. Int J Cancer 134:2403–2413

    Article  CAS  PubMed  Google Scholar 

  36. Shen L, Zhang H, Liang L et al (2014) Baseline neutrophil-lymphocyte ratio (≥2.8) as a prognostic factor for patients with locally advanced rectal cancer undergoing neoadjuvant chemoradiation. Radiat Oncol 9:295

    Article  PubMed  PubMed Central  Google Scholar 

  37. Kim IY, You SH, Kim YW (2014) Neutrophil-lymphocyte ratio predicts pathologic tumor response and survival after preoperative chemoradiation for rectal cancer. BMC Surg 14:94

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This study was supported in part by Grant 15 K11295 from the Ministry of Education, Culture, Sports, Science and Technology in Japan to S. Yanamoto. We would like to thank Editage (http://www.editage.jp/) for English-language editing.

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Authors and Affiliations

  1. Department of Clinical Oral Oncology, Unit of Translational Medicine, Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki, 852-8588, Japan

    Kenichi Shinagawa, Souichi Yanamoto, Tomofumi Naruse, Akiko Kawakita, Kota Morishita, Yuki Sakamoto, Satoshi Rokutanda & Masahiro Umeda

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  1. Kenichi Shinagawa
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  2. Souichi Yanamoto
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  3. Tomofumi Naruse
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  4. Akiko Kawakita
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  7. Satoshi Rokutanda
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  8. Masahiro Umeda
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Correspondence to Souichi Yanamoto.

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The authors have no conflicts of interests to declare in this study.

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Shinagawa, K., Yanamoto, S., Naruse, T. et al. Clinical Roles of Interleukin-6 and STAT3 in Oral Squamous Cell Carcinoma. Pathol. Oncol. Res. 23, 425–431 (2017). https://doi.org/10.1007/s12253-016-0134-x

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  • DOI: https://doi.org/10.1007/s12253-016-0134-x

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